Dr. Bailey-Wilson has been working for over 30 years to detect genetic risk factors for lung cancer and possible gene-gene and/or gene-environment interactions. The purpose of her study of lung cancer is to identify a gene or genes that contribute to lung cancer susceptibility. In this fiscal year, family data have been collected in Louisiana. Data collection is expected to continue for several more years. Dr. Bailey-Wilson is a founder of the Genetic Epidemiology of Lung Cancer Consortium (GELCC) for the purpose of obtaining additional family data from a large group of collaborative investigators. The first genome-wide significant linkage of a lung cancer susceptibility locus on chromosome 6q was published by us. A paper characterizing the linkage evidence after using ordered subset analysis was also published by us using smoking and other linkage regions as the ordering variable. This work suggested that several additional variants may increase risk for lung cancer in these highly aggregated families. We have previously published evidence that RGS17 is a tumor suppressor gene that is associated with LC risk; it may be involved in explaining part but not all of the 6q linkage signal. We also published additional sequencing studies of the region along with studies of a knock-out mouse model (in the lab of collaborator Ming You), suggesting that PARK2 may also harbor risk variants in some of our families. A new set of families was recently genotyped for a SNP marker linkage panel and were analyzed with novel linkages detected and published. A large GWAS on familial cases vs elderly, smoking controls was genotyped at the Center for Inherited Disease Research and the results were published this year (2). We are analyzing targeted sequence data in the 6q region in our most strongly linked families and analyses are ongoing. We have performed whole exome sequencing in collaboration with Dr. Margaret Spitz of Baylor University on 60 of our family-history-positive patients with several papers published. We received whole exome sequencing data on about 100 affected relatives in our highly aggregated families from Dr. Ramaswamy Govindan, Washington University and WES sequencing was recently completed on additional families at the NHGRI NISC lab. We have performed joint alignment and variant calling on all three of our sets of WES data and analyzed these families. A paper presenting the results is under review. Another paper presenting the 6q targeted sequencing results is in preparation. The GELCC consortium has just received a very favorable grant review (1st percentile) for continuing the sequencing studies in these families and Dr. Bailey-Wilson will continue to collaborate with GELCC investigators (as an unpaid collaborator). Another major aim of Dr. Bailey-Wilson's research is to determine genetic risk factors in families with human prostate cancer. Papers published previously by our large group of collaborators have shown evidence of PRCA susceptibility genes in regions of chromosomes 1 (HPC1), 3p, 11q, 8 and Xq (HPCX). These results have been followed up by intensive linkage analyses of additional families to markers in these regions and in other regions that showed some mild evidence of linkage in the initial genome scans. Previously, our group identified mutations in the ribonuclease-L (RNASEL) gene as being the locus in our chromosome 1 linkage region (HPC1) causing increased risk to prostate cancer and showed evidence that mutations in the MSR1 gene on chromosome 8 plays a role in prostate cancer risk. In collaboration with Dr. Johanna Schleutker's group, we published new linkage analyses confirming linkage on chromosome 17 in a set of highly aggregated Finnish prostate cancer families. Some of our collaborators in the International Consortium for Prostate Cancer Genetics showed that HOXB13 is a good candidate for this locus and, follow-up in Finland and in the ICPCG families support this as a causal locus. on analyzing fine-mapping and sequence data in the African-American Hereditary Prostate Cancer (AAHPC) families. We work with the International Prostate Cancer Genetics Consortium (ICPCG) to try to localize prostate cancer loci more rapidly. We are also collaborating with Dr. Diptasri Mandal on linkage studies of prostate cancer in African-American men from Louisiana. We successfully competed for WES sequencing in these data and the data are currently being analyzed by us. In addition to the ongoing linkage studies, the ICPCG is performing whole exome sequencing studies in our highly-aggregated prostate cancer families and Dr. Deyana Lewis (a fellow in my group) is working on analysis of these data in the AAHPC families. She is also working with one of my former fellows, Dr. Cheryl Cropp, who is now an Assistant Professor at Samford University and a Guest Researcher at SGS, to co-lead the ICPCG analyses of AA families. Dr. Lewis successfully competed for a Coleman research award based on the AAHPC sequencing study. Dr. Bailey-Wilson is working on a collaborative study of Carcinoid tumor with Drs. Steven Wank of NIDDK. In this study of this rare familial tumor, we are comparing linkage results in several large, highly aggregated families with whole-exome sequence data to attempt to localize genes responsible for this highly-penetrant familial tumor. In one of these families, our linkage analyses were used to localize a causal variant shared by all affecteds and cosegregating with disease in the large family. Dr. Wanks group has characterized this variant and shown that it is causal, and a paper presenting these results was published in 2015. We are now proceeding with additional linkage and whole genome sequence analysis of additional carcinoid tumor families. We have started a collaboration with Dr. Henry Lynch and his group at Creighton University on two projects. First, we successfully competed for WES sequencing at NISC to search for germline mutations in families with multiple individuals affected with melanoma or pancreatic cancers but with unknown mutational status. These samples are currently being sequenced and will be analyzed next year. In the second project, Dr. Candace Middlebrooks, a fellow in my group, is performing survival analyses on families with known germline mutations in high risk cancer genes to determine what additional cancers show increased risk in carriers of the mutations. One paper presenting the results in families with mutations in CDKN2A was published this year (2), a paper presenting our analyses of BRCA1 mutation families is in preparation and analyses of BRCA2 mutation families is ongoing. We have started a new collaboration with Dr. Athena Starlard-Davenport at University of Tennessee Health Sciences Center on breast cancer interactions. Drs. Lewis and Middlebrooks will be working with her on these projects and we were recently successful in competing for centrally-funded whole genome sequencing of participants in this breast cancer study. We expect this sequencing to occur next year.